This invention relates to cephalosporin antibiotics and, in particular, to processes for the preparation of crystalline cephalexin intermediates useful for the production of cephalexin hydrochloride monohydrate.
Cephalexin is the generic term used to identify the chemical compound 7-(D-2-amino-2-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid. That compound is described in U.S. Pat. No. 3,507,861. Later patents including U.S. Pat. Nos. 3,655,656 and 3,781,282 have described processes for preparing unique forms of cephalexin. The '656 patent describes a process for preparing cephalexin monohydrate which is a highly crystalline dense form of cephalexin ideally suited to formulation into capsules and tablets for human therapy. U.S. Pat. No. 3,781,282 describes and claims cephalexin bis(N,N-dimethylformamide) solvate, a valuable crystalline intermediate for the production of cephalexin and cephalexin derivatives.
While cephalexin monohydrate has enjoyed widespread commercial success as a 2-4 times a day treatment for bacterial infections, that form of cephalexin has relatively low water solubility. The relatively low water solubility of cephalexin monohydrate may, in some instances, delay its absorption so that the high blood levels achievable with cephalexin are not immediately realized following administration of conventional cephalexin monohydrate formulations.
Recently it has been found that crystalline cephalexin hydrochloride monohydrate exhibits much improved solubility characteristics over that of cephalexin monohydrate. That particular crystalline form of cephalexin, cephalexin hydrochloride monohydrate, is prepared by exposing crystalline cephalexin hydrochloride ethanol solvate (ethanolate) to an atmosphere having a relative humidity of about 10 to about 50 percent. The ethanol solvate intermediate used to prepare the more soluble cephalexin hydrochloride monohydrate is obtained from ethanol solutions of cephalexin hydrochloride formed by treating suspensions of cephalexin monohydrate in ethanol with gaseous hydrogen chloride.
An object of this invention is to provide an improved method for the preparation of crystalline cephalexin hydrochloride C.sub.1 -C.sub.2 alkanolates, useful intermediates for the production of crystalline cephalexin hydrochloride monohydrate.
A further object is to provide a high yielding method for preparation of cephalexin hydrochloride isopropanolate from the art-recognized cephalexin bis-dimethylformamide solvate.
Another object of this invention is to provide a method for preparing two crystalline forms of cephalexin, novel cephalexin ethanolate and desolvated cephalexin ethaholate, from cephalexin bis-dimethylformamide solvate. Those crystalline forms of cephalexin can be used as starting materials in the present improved method for the preparation of cephalexin hydrochloride alcoholates.